Drug Delivery Apparatus and Method for Automatically Reducing Drug Dosage

ABSTRACT

A drug delivery device which includes a fluid drug reservoir, a catheter, a controllable fluid transfer device, e.g., a pump mechanism or valve, and a drug delivery control means. The drug delivery control means comprises a controller, e.g., a microprocessor or microcontroller which is operable to automatically reduce the rate of drug delivery over a certain reduction interval (e.g., multiple days) from an initial dosage value to a final dosage value.

RELATED APPLICATIONS

This application is a CIP of U.S. application Ser. No. 11/069,573 filedon 28 Feb. 2005 which is incorporated herein by reference. Thisapplication claims the benefit of U.S. Provisional Application60/604,999 filed on 27 Aug. 2004 which is incorporated herein byreference.

FIELD OF THE INVENTION

This invention relates generally to medical devices for delivering amedication, or drug, to a body site at flow rates and times specified bya stored drug delivery profile. More particularly, this inventionrelates to such devices which can operate to automatically graduallymodify rates of drug delivery to achieve a desired target dosage.

BACKGROUND OF THE INVENTION

Various implantable drug delivery devices are known in the art which canbe programmed to deliver a drug to a body site for infusion at flowrates and times dictated by a stored drug delivery profile. Suchdelivery devices typically include a refillable reservoir for storing afluid drug and a controllable fluid transfer device (e.g., a pump orvalve) for transferring fluid from the reservoir to a catheter fordelivery to the body site. The drug delivery profile comprises a dataset specifying a schedule of flow rates for a periodic cycle, or period,of a certain duration. For example, the duration of a period can betwelve hours, twenty four hours, or one week, etc. The particularprofile used to control drug delivery is typically specified by thepatient's clinician and depends upon several factors including theparticular drug formulation being delivered, the patient's condition,the therapy being administered, etc.

The delivery profile is typically stored in the medical device at thetime of implanting and can thereafter be modified by a clinician (usingan external controller or programmer) when the patient periodicallyvisits for a refill/checkup, e.g., once per month.

In the course of certain drug therapies, it may be desirable to increaseor reduce the drug dosage delivered to the patient. For example, in somesituations, it may be helpful to reduce or terminate drug administrationfor a limited period in order to increase the patient's sensitivity tothe drug. In still other situations, it may be desirable to terminatedelivery of a drug as an initial step in preparation for changing thedrug formulation.

For illustrative purposes, in situations where a therapeutic decisionhas been made to reduce or eliminate delivery of a certain drug, it isgenerally desirable to reduce the drug dosage gradually. This gradualreduction, which is sometimes referred to as a detoxification procedure,is relatively easy to administer if the patient is available to theclinician on a frequent basis, e.g., daily. However, in the use ofimplanted drug delivery devices, patients typically visit theirclinicians infrequently, e.g., once per month, and it has therefore beeninconvenient and impractical to administer a drug modification program.The present invention is directed to an implantable drug deliveryapparatus and method of operation which facilitates the automaticgradual modification, e.g., reduction of drug delivery over an extendedinterval, e.g., many days.

SUMMARY OF THE INVENTION

The present invention relates to a drug delivery device which includes afluid drug reservoir, a catheter, a controllable fluid transfer device,e.g., a pump or valve mechanism, and a drug delivery controller. Thecontroller, e.g., a microprocessor, is operable in accordance with theinvention, to automatically gradually reduce the rate of drug deliveryspecified by a stored delivery profile from a current dosage value to atargeted final dosage value.

In accordance with a preferred embodiment, dosage reduction is achievedover an interval comprised of multiple periods, where a period may, forexample, comprise 4, 12, or 24 hours. An initial delivery profilespecifies an initial delivery rate (or rates). Delivery rates for eachsubsequent period within the reduction interval are determined byapplying a calculated reduction rate (typically a percentage) to thedelivery profile for the preceding period. In this manner, the initialdelivery profile is incrementally reduced in steps to ultimately achievea delivery profile specifying the desired final dosage value.

For example, in a preferred embodiment, a clinician may specify a finaldosage value and the duration of the reduction interval (which can beexpressed in number of periods). Based on this information and theinitial dosage information contained in the stored initial deliveryprofile, a system in accordance with the invention operates to calculatea reduction rate which is then used to periodically reduce the deliveryrates until the rates appropriate to the final dosage value are reached.

The preferred embodiment also enables the clinician to alternativelyspecify a periodic (e.g., daily) dosage reduction rate thus enabling thesystem to then calculate the duration of the reduction interval (e.g.,number of days).

Although in many applications, it suffices to calculate and reducedelivery rates on a daily basis, it is recognized that for more rapiddosage reduction, or detoxification, delivery rates can be reduced morefrequently by partitioning the 24 hour daily period into subperiods of,for example, 2 hours, 4 hours, or 8 hours.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a block diagram of an exemplary medical system comprised of animplantable medical device, e.g., a drug delivery device, and anexternal communication device, or programmer;

FIG. 2 is a schematic diagram of an exemplary implantable drug deliverydevice;

FIG. 3A shows an exemplary initial drug delivery profile for a 24 hourperiod and successive reductions of said profile in accordance with theinvention;

FIG. 3B plots the daily dosage delivered to the patient with respect toFIG. 3A over the full reduction interval showing a reduction of deliveryrate occurring once every 24 hours;

FIG. 3C is similar to FIG. 3B but depicts the full reduction of deliveryrate occurring once every four hours rather than once per day;

FIG. 4 is a flow chart depicting an algorithm executable by an externalprogrammer for producing data for an implanted drug delivery device toenable the device to gradually reduce the dosage, i.e., rate of drugdelivery, to the patient; and

FIG. 5 is a flow chart executable by the implanted drug delivery device.

DETAILED DESCRIPTION

Attention is initially directed to FIG. 1 which presents a generalizedblock diagram of a medical system 10 comprised of at least one medicaldevice 14, e.g., an implantable drug delivery device and an externalcommunication device or programmer 16. The system of FIG. 1 isconfigured to enable the medical device 14 and the programmer 16 tocommunicate, e.g., via RF telemetry 17, using telemetry subsystem 18 andtelemetry subsystem 19, respectively contained within the devices 14 and16. The medical device 14 will be assumed herein to comprise a pumpimplanted in a patient's body for the purpose of delivering a fluid drugto a body site. The programmer 16, on the other hand, is intended to bedeployed external to the body and available for use by a physician orclinician or patient to transmit control and/or data signals to thedevice 14. For example, using the programmer 16, a clinician is able toproduce signals which are transmitted via RF link 17 to the medicaldevice 14 to affect its therapeutic performance such as by modifying itsdrug delivery profile. Systems of the type depicted in FIG. 1, as thusfar described are well known. The present invention is directed to amethod and apparatus particularly configured to automatically modify astored delivery profile to reduce the rate of drug delivery to thepatient.

As depicted in FIG. 1, a typical medical device 14 in system 10 includesan internal power source 20, e.g., a battery, a controller 22 (sometimeshereinafter referred to as a microprocessor), and a memory 24 associatedtherewith for storing programs and/or data. The microprocessor 22operates to execute a stored program to control therapeutic subsystem 26to controllably deliver a drug to a patient's body site. The device 14may also include an alarm subsystem 28 controllable by microprocessor 22to alert the patient or clinician of some monitored event.

Programmer device 16 is shown as including a controller 34 (sometimeshereinafter referred to as a microprocessor which operates inconjunction with memory 35 which stores programs and/or data. The device16 optionally includes a user input device 36, e.g., a keyboard, and auser output device 37, e.g., a display. The programmer 16 furtherinclude aforementioned telemetry subsystem 19 configured to transmitsignals to or receive signals from the medical device telemetrysubsystem 18. The programmer 16 may further include an internal powersource 38 which can comprise a battery or any other suitableconventional power source.

In a typical system 10, the programmer 16 is capable of sending messagesto the medical device 14 for use by microprocessor 22 to affect theoperation of its therapeutic administration subsystem 26. Additionally,the medical device 14 is typically capable of sending messages to thecommunication device 16 to report various conditions, e.g., batterystatus, drug reservoir status, etc. These respective messages sent bythe programmer 16 and medical device 14 are handled by the respectivetelemetry subsystems 19 and 18, each of which is able to transmit andreceive RF telemetry signals. Typically, these RF telemetry signalscomprise bit streams carried by an RF carrier signal of specifiedfrequency.

FIG. 2 illustrates a typical implantable drug delivery device, or pump,14 comprising a sealed housing 41 defining an interior volume 42. Areservoir 43 for storing a drug to be delivered is mounted in thehousing 41 and has an inlet coupled to a fill port 44. A controllablefluid transfer device 45, e.g., a pump or valve mechanism, couples areservoir outlet via tube 46 to the proximal end 47 of a catheter 48.The catheter distal end 49 is intended to be implanted proximate to atarget site in the patient's body for delivering the drug thereto. FIG.2 also shows a controller 50 for controlling the fluid transfer device45. Controller 50 corresponds to controller 22 and associated elementsshown in device 14 in FIG. 1.

In typical use, a hypodermic needle (not shown) is used, via fill port44, to fill the reservoir 43 with a first drug. The fluid transferdevice 45 is controlled by controller 50 in accordance with a storeddrug delivery profile comprising a set of data which specifies aschedule of drug flow rates over a certain period, e.g., having aduration of twenty four hours.

FIG. 3A depicts an exemplary initial daily drug delivery profile 52defined by data stored in controller 50. Profile 52 specifies a firstdelivery rate 53 from 00:00 to 06:00 hours and from 22:00 to 00:00 hoursand a second delivery rate 54 from 06:00 to 22:00 hours. The exemplaryvalues of the first and second delivery rates are respectivelyrepresented in FIG. 3A as 7 and 8 strokes per minute where “strokes perminute” refers to the activity of pump mechanism 45 (FIG. 2). Thus, itcan be seen that the profile 52 will cause the pump to produce 11040strokes/day (i.e., 7 strokes/minute×60 minutes/hour×8 hours)+(8strokes/minute×60 minutes/hour×16 hours). If we assume that pump 40moves 0.25 microliters of drug per stroke, then the drug dosage, ordaily quantity delivered to the patient will equal 2.76 milliliters/day(i.e., 11040 strokes×0.25 microliters/stroke).

When a dosage reduction operation is initiated in accordance with thepresent invention, the profile 52 is iteratively processed tosuccessively produce profiles 55, 56, 57, 58, etc. of diminishingamplitude.

FIG. 3B depicts the resulting dosage reduction over a multi-dayreduction interval. For example, FIG. 3B shows how the daily deliveryrate is reduced from an initial value to a final value (shown as zero)over a 14 day interval. Whereas FIG. 3B shows the rate reductionsoccurring only once per day (i.e., 24 hour period), FIG. 3C demonstratesrate reductions occurring more frequently, e.g., once per 4 hour period.

Attention is now directed to FIG. 4 which comprises a flow chartdepicting the functioning of programmer 16 when operated by a clinicianto run the automatic drug delivery reduction mode in accordance with thepresent invention. Block 100 functionally represents the patient'speriodic (e.g., monthly) visit to the clinician's office for a checkupand/or drug refill. Block 102 represents the programmer 16 initiatingcommunication with the implanted medical device, or pump, 14 to readstatus data (including the current drug delivery profile) from thepump's memory 24. Block 104 represents the clinician initiating a dosagereduction, i.e., detoxification operational mode in accordance with theinvention.

Before proceeding with the description of the flow chart of FIG. 4, itwould be helpful to define certain terms and mathematically develop thetask to be accomplished. Let the following parameters by represented bythe indicated terms:

D₀=Initial daily dosage (ML/day)

D_(N)=Daily dosage on day N (ML/day)

R_(day)=Daily reduction rate (%/day)

R_(P)=Periodic reduction rate (%/pd.)

P=Reduction period (hours)

R_(R)=Periodic reduction ratio (1−R_(P)) (%)

N=Reduction interval (days)

Then

D ₁ =D ₀*(1−R _(day))

D ₂ =D ₀*(1−R _(day))*(1−R _(day))

D _(N) =D ₀*(1−R _(day))^(N)  (1)

If the initial D₀ and final D_(N) daily dosages are known and it isdesired that the reduction occur over a fixed reduction interval,equation (1) can be rewritten to find the daily reduction rate.

R _(day)=1−(D _(N) /D ₀)^(1/N)  (2)

If the reduction rate R_(day), initial dosage D₀, and final dosage D_(N)are known, this equation can be solved for the number of days N.

(1−R _(day))=(D _(N) /D ₀)^(1/N)

Log(1−R _(day))=Log(D _(N) /D ₀)^(1/N)

N Log(1−R _(day))=Log(D _(N) /D ₀)

N=Log(D _(N) /D ₀)/Log(1−R _(day))  (3)

For rapid dosage reduction, it is possible to reduce the dosage severaltimes a day instead of once a day. If this is done, it is still possibleto specify the total daily reduction as either a percentage or a ratio.The following equation shows how to convert from a daily reduction ratioto a reduction ratio that is applied every P hours.

From Equation (1):

D ₁ =D ₀*(1−R _(day)) for a daily reduction

D ₁ =D ₀*(1−R _(P))^(24/P) for a reduction every P hours

Therefore:

D ₀*(1−R _(day))=D ₀*(1−R _(P))^(24/P)

(1−R _(day))=(1−R _(P))^(24/P)

(1−R _(day))^(P/24)=(1−R _(P))

R _(P)=1−(1−R _(day))^(P/24)  (4)

The periodic reduction ratio is that fraction by which each deliveryrate in the delivery profile is multiplied at the beginning of everyreduction interval (P). This is shown in equation (5).

R _(R)=(1−R _(day))^(P/24)  (5)

With continuing reference to FIG. 4, block 106 calls for the clinicianto enter a final daily dosage value D_(N) and either a daily reductionrate R_(day) or the reduction interval in days N. Block 108 calls forthe programmer microprocessor 34 to read the current dosage value D₀which was retrieved from the pump 14 as part of the current profile inblock 104.

Decision block 110 asks if the reduction rate R_(day) was specified. IfYES, operation branches to decision block 112 which asks if the finaldosage value D_(N) is less than 0.05 times the initial dosage value D₀.If YES, block 114 is executed to adjust the final dosage value D_(N) to0.05 times D₀. This operation is performed to terminate profilereduction at a value of D_(N) which is clinically insignificant butgreater than zero. If profile reduction were allowed to continue untilD_(N) reached zero, the reduction would iterate indefinitely inattempting to asymptotically reach zero. Operation then proceeds toblock 116 which computes aforementioned equation (3) to determine thereduction interval N. If decision block 112 yielded a NO, block 114 isskipped.

If decision block 110 yields a NO, operation proceeds to block 118 whichcomputes aforementioned equation (2) to determine the daily reductionrate R_(day).

From either block 116 or 118, operation proceeds to block 120 whichcomputes aforementioned equation (5) to determine the periodic reductionratio R_(R). Thereafter (block 122), the programmer 16 transmits variousvalues to reprogram the pump 14 including periodic reduction ratioR_(R), reduction period P, and the reduction interval N. This action(block 124) completes the activity of the programmer in the execution ofthe automatic dosage reduction mode in accordance with the invention.

Attention is now directed to FIG. 5 which depicts a flow chartdescribing the operation of the pump microprocessor 22 in the executionof the automatic dosage reduction mode. The flow chart of FIG. 5 startswith block 200 which represents the pump 14 having been reprogrammed bythe operation depicted in FIG. 4. Block 201 calculates the number ofreduction steps required. For the sake of clarity in explanation, atypical example will be assumed in which the dosage reduction, or detox,interval will have a duration N of fourteen days and the reductionperiod P will have a duration of four hours. This assumed example (FIG.3C) will, of course, require eighty four (i.e., N×24/P) reduction stepsto reach the desired final dosage value.

Block 202 sets a timer (MinutesTillRed) to a count value equal to sixtytimes the reduction period P. The microprocessor 22 can then sleep(block 204) to conserve power until the beginning of the next minute.The MinutesTillRed count is then decremented by one minute (block 206).

Decision block 208 then asks is the MinutesTillRed count equal to zero,or in other words, is it now time to reduce the delivery rate. If NO,operation loops back to block 204. Operation continues to loop throughblocks 204, 206, 208 until decision block 208 yields a YES. A YES resultfrom block 208 resets the MinutesTillRed count (block 210) to 60×P.

Block 214 then executes one reduction step by multiplying each rate inthe current profile by the periodic reduction ratio R_(R); i.e., Rate(n)=Rate (n) times R_(R). Since R_(R) always has a value less than one,this multiplication will, of course, reduce the value of Rate (n) in theup-dated current profile.

Block 216 then decrements the RedStop count by one. Block 218 then asksif the RedStop count is equal to zero. If NO, operation loops back toblock 204. If YES, operation proceeds to block 220 which allows the pump14 to continue to deliver drug in accordance with the current updatedprofile.

From the foregoing, it should now be understood that a drug deliveryapparatus and method of operation has been disclosed herein forautomatically and gradually reducing delivery rates. Although only asingle preferred exemplary embodiment has been described, it is intendedthat the appended claims be interpreted to encompass variations andmodifications which will be apparent to those persons skilled in theart.

1-16. (canceled)
 17. An implantable drug delivery device, comprising: animplantable housing configured for implantation into a body; a reservoirwithin the implantable housing; a fluid transfer device within theimplantable housing in fluidic communication with the reservoir; andmeans, carried within the implantable housing, for repeatedly modifyingan entire stored delivery profile including at least one delivery ratein response to a single receipt of modification data.
 18. An implantabledrug delivery device as claimed in claim 17, wherein the stored deliveryprofile includes at least two different delivery rates.
 19. Animplantable drug delivery device as claimed in claim 17, wherein thestored delivery profile includes a plurality of delivery rates, at leasttwo of which are different, that are associated with respective portionsof a 24-hour period.
 20. An implantable drug delivery device as claimedin claim 17, wherein the stored delivery profile comprises a deliveryprofile for a 24-hour period.
 21. An implantable drug delivery device asclaimed in claim 17, wherein the at least one delivery rate is definedin terms of pump strokes.
 22. An implantable drug delivery device asclaimed in claim 17, wherein the modification data comprises a reductionratio having a value that is less than
 1. 23. A method of operating animplantable drug delivery device, comprising the step of: repeatedlymodifying a delivery profile that includes a plurality of delivery ratesand is stored within the implantable drug delivery device with theimplantable drug delivery device in response to a single receipt ofwirelessly transmitted modification data.
 24. A method as claimed inclaim 23, further comprising the step of: receiving wirelesslytransmitted modification data with the implantable drug delivery devicewhile the entire implantable drug delivery device is carried within apatient's body.
 25. A method as claimed in claim 23, wherein the step ofrepeatedly modifying a stored delivery profile comprises performing thefollowing steps with the implantable drug delivery device in response toa single receipt of wirelessly transmitted modification data: (1)creating a modified delivery profile by reducing the delivery rates inthe stored delivery profile, (2) storing the modified delivery profilefor a predetermined period, and (3) repeating steps (1) and (2) afterthe expiration of the predetermined period.
 26. A method as claimed inclaim 25, wherein the predetermined period is at least about 2 hours.27. A method as claimed in claim 25, wherein the predetermined period isbetween about 2 hours and about 24 hours.
 28. A method as claimed inclaim 25, wherein the modification data comprises a reduction ratiohaving a value less than 1.0; and the step of creating a modifieddelivery profile comprises multiplying the delivery rates in thedelivery profile by the reduction ratio.
 29. A method as claimed inclaim 25, wherein the step of repeating steps (1) and (2) comprisesrepeating steps (1) and (2) after the expiration of the predeterminedperiod a plurality of times over the course of a plurality of days inresponse to a single receipt of wirelessly transmitted modificationdata.
 30. A method of modifying the dosage of a drug supplied by a drugdelivery device that stores a delivery profile including at least onedelivery rate and is located entirely within a patient, the methodcomprising the steps of: wirelessly transmitting a final daily dosagevalue to the drug delivery device located entirely within the patient;wirelessly transmitting a reduction rate or a reduction interval to thedrug delivery device located entirely within the patient; and allowingthe drug delivery device located entirely within the patient to itselfiteratively reduce the at least one delivery rate over the course of aplurality of days as a function of the transmitted final daily dosagevalue and the transmitted reduction rate or as a function of thetransmitted final daily dosage value and the transmitted reductioninterval.
 31. A method as claimed in claim 30, wherein the final dosagevalue is expressed in terms of volume per time period.
 32. A method asclaimed in claim 30, wherein the final dosage value is expressed interms of volume per day.
 33. A method as claimed in claim 30, whereinthe reduction rate is expressed as a percentage reduction per timeperiod or a reduction ratio per time period.
 34. A method as claimed inclaim 30, wherein the reduction rate is expressed as a percentagereduction per day or a reduction ratio per day.
 35. A method as claimedin claim 30, wherein the reduction interval is expressed in days.
 36. Amethod of operating an implantable drug delivery device, comprising thesteps of: initiating a dosage reduction mode in response to a singleevent; and modifying a delivery profile that includes one or moreclinically significant delivery rates and is stored within theimplantable drug delivery device by reducing the one or more clinicallysignificant delivery rates to one or more lower clinically significantdelivery rates with the implantable drug delivery device in response tothe initiation of the dosage reduction mode.
 37. A method as claimed inclaim 36, where in the step of initiating a dosage reduction modecomprises initiating a dosage reduction mode in response to a singlereceipt of wirelessly transmitted modification data.
 38. A method asclaimed in claim 36, where in the step of modifying a delivery profilecomprises repeatedly modifying a delivery profile that includes one ormore clinically significant delivery rates and is stored within theimplantable drug delivery device by reducing the one or more clinicallysignificant delivery rates to one or more lower clinically significantdelivery rates with the implantable drug delivery device in response tothe initiation of the dosage reduction mode.
 39. A method as claimed inclaim 36, where in the step of modifying a delivery profile comprisesmodifying a delivery profile that includes a plurality of clinicallysignificant delivery rates and is stored within the implantable drugdelivery device by reducing the plurality of clinically significantdelivery rates to a plurality of lower clinically significant deliveryrates with the implantable drug delivery device in response to theinitiation of the dosage reduction mode.